There has been significant progress in the discovery and development of potential neuropharmaceuticals (small molecules, peptides, proteins, and antisense) for treating pain and brain disorders such as Alzheimer's and Parkinson's diseases over the last decade. However, systemic delivery of many newly discovered neuropharmaceuticals has been hampered by the lack of an effective system for delivering them. Intravenous injection is usually ineffective because of inadequate transport across the barrier between the brain and the blood supply (the “blood-brain barrier” or “BBB”). The blood-brain barrier is a continuous physical barrier that separates the central nervous system, i.e., the brain tissue, from the general circulation of an animal. The barrier is comprised of microvascular endothelial cells that are joined together by complex tight intracellular junctions. This barrier allows the selective exchange of molecules between the brain and the blood, and prevents many hydrophilic drugs and peptides from entering into the brain. Many of the new potent neuroactive pharmaceuticals do not cross the BBB because they have a molecular weight above 500 daltons and are hydrophilic. Compounds that are non-lipophilic and have a molecular weight greater than 500 daltons generally do not cross the BBB.
Several strategies for delivering high molecular weight, non-lipophilic drugs to the brain have been developed including intracerebroventricular infusion, transplantation of genetically engineered cells that secrete the neuroactive compound, and implantation of a polymer matrix containing the pharmaceutical. See Pardridge, W. M., J. Controlled Rel., (1996) 39:281-286. However, all of these involve invasive surgical procedures that can entail a variety of complications.
Four nonsurgical transport mechanisms have been identified for crossing the BBB, including: (i) transmembrane diffusion, (ii) receptor-mediated transport, (iii) absorptive-mediated endocytosis, and (iv) carrier-mediated transport. See Brownless et al., J. Neurochemistry, (1993) 60(3):793-803. Vascular permeability can be increased by opening the tight junctions with hyperosmotic saccharide solutions and analogs of bradykinin. An inherent problem in this method is that undesirable compounds in the general circulation may enter the brain through the artificially enlarged openings in the blood-brain barrier.
It has been discovered that capillary endothelial cells in the blood-brain barrier have a high level of receptors to transferrin, insulin, insulin-like growth factor I and II, low-density lipoprotein and atrial natriuretic factor. See Friden, P. M., J. Controlled Rel., (1996) 46:117-128. U.S. Pat. No. 5,833,988 to Friden describes a method for delivering a neuropharmaceutical or diagnostic agent across the blood-brain barrier employing an antibody against the transferrin receptor. A nerve growth factor or a neurotrophic factor is conjugated to a transferrin receptor-specific antibody. The resulting conjugate is administered to an animal and is capable crossing the blood-brain barrier into the brain of the animal.
U.S. Pat. No. 4,902,505 to Pardridge et al. describes the use of chimeric peptides for neuropeptide delivery through the blood-brain barrier. A receptor-specific peptide is used to carry a neuroactive hydrophilic peptide through the BBB. The disclosed carrier proteins, which are capable of crossing the BBB by receptor-mediated transcytosis, include histone, insulin, transferrin, insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), basic albumin, and prolactin. U.S. Pat. No. 5,442,043 to Fukuta et al. discloses using an insulin fragment as a carrier in a chimeric peptide for transporting a neuropeptide across the blood-brain barrier.
Non-invasive approaches for delivering neuropharmaceutical agents across the BBB are typically less effective than the invasive methods in actually getting the agent into the brain. High doses of the chimeric peptides are required to achieve the desired therapeutic effect because they are prone to degradation. The concentration of the chimeric peptides in the blood circulation can be quickly reduced by proteolysis. An aqueous delivery system is not generally effective for delivering hydrophobic drugs.
Another method for delivering hydrophilic compounds into the brain by receptor-mediated transcytosis is described by Pardridge et al. in Pharm. Res. (1998) 15(4):576-582. A monoclonal antibody to the transferrin receptor (OX26 MAb) modified with streptavidin is used to transport the cationic protein, brain-derived neurotrophic factor (BDNF) through the BBB. BDNF is first modified with PEG2000-biotin to form BDNF-PEG2000-biotin, which is then bound to the streptavidin-modified antibody OX26 MAb. The resulting conjugate was shown to be able to cross the BBB into the brain.
Enhancing the duration of antinociceptive effects in animals may result in less frequently administered analgesics, which can improve patient compliance and reduce potential side effects. Maeda et al. in Chem. Pharm. Bull. (1993) 41(11): 2053-2054, Biol. Pharm Bull. (1994) 17(6):823-825, and Chem. Pharm. Bull. (1994) 42(9):1859-1863 demonstrate that by attaching polyethylene glycol amine 4000 to the C-terminal leucine of Leu-enkephalin (distant from the tyrosine residue needed for antinociception), they could increase the potency and duration of Leu-enkaphalin when it was directly administered to the brain by intracerebroventricular injection.
There is a need in the art for an improved method to deliver neuroactive agents from the systemic circulation across the blood-brain barrier and into the brain that reduces or eliminates some of the drawbacks and disadvantages associated with the prior art.